In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or... Show moreIn the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naive B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers. Show less
IntroductionAspergillus fumigatus (Asp) infections constitute a major cause of morbidity and mortality in patients following allogeneic hematopoietic stem cell transplantation (HSCT). In the... Show moreIntroductionAspergillus fumigatus (Asp) infections constitute a major cause of morbidity and mortality in patients following allogeneic hematopoietic stem cell transplantation (HSCT). In the context of insufficient host immunity, antifungal drugs show only limited efficacy. Faster and increased T-cell reconstitution correlated with a favorable outcome and a cell-based therapy approach strongly indicated successful clearance of fungal infections. Nevertheless, complex and cost- or time-intensive protocols hampered their implementation into clinical application. MethodsTo facilitate the clinical-scale manufacturing process of Aspergillus fumigatus-specific T cells (ATCs) and to enable immediate (within 24 hours) and sustained (12 days later) treatment of patients with invasive aspergillosis (IA), we adapted and combined two complementary good manufacturing practice (GMP)-compliant approaches, i) the direct magnetic enrichment of Interferon-gamma (IFN-gamma) secreting ATCs using the small-scale Cytokine Secretion Assay (CSA) and ii) a short-term in vitro T-cell culture expansion (STE), respectively. We further compared stimulation with two standardized and commercially available products: Asp-lysate and a pool of overlapping peptides derived from different Asp-proteins (PepMix). ResultsFor the fast CSA-based approach we detected IFN-gamma(+) ATCs after Asp-lysate- as well as PepMix-stimulation but with a significantly higher enrichment efficiency for stimulation with the Asp-lysate when compared to the PepMix. In contrast, the STE approach resulted in comparably high ATC expansion rates by using Asp-lysate or PepMix. Independent of the stimulus, predominantly CD4(+) helper T cells with a central-memory phenotype were expanded while CD8(+) T cells mainly showed an effector-memory phenotype. ATCs were highly functional and cytotoxic as determined by secretion of granzyme-B and IFN-gamma. DiscussionFor patients with IA, the immediate adoptive transfer of IFN-gamma(+) ATCs followed by the administration of short-term in vitro expanded ATCs from the same donor, might be a promising therapeutic option to improve the clinical outcome. Show less
Background: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age at onset... Show moreBackground: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age at onset present challenges for patient management. Objective: We sought to characterize the phenotype, treatment, and survival outcomes of XIAP deficiency and to assess parameters influencing prognosis. Methods: Data published from 2006 to 2020 were retrospectively analyzed. Results: A total of 167 patients from 117 families with XIAP deficiency were reported with 90 different mutations. A wide spectrum of clinical features were seen, of which hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease were the most common. Patients frequently developed multiple features with no clear genotype-phenotype correlation. A total of 117 patients were managed conservatively and 50 underwent hematopoietic stem-cell transplantation (HSCT), with respective overall survival probabilities of 90% and 53% at age 16 years. The predominant indication for HSCT was early-onset HLH. Active HLH and myeloablative conditioning regimens increased HSCT-related mortality, although HSCT outcome was much better after 2015 than before. For conservatively managed patients reaching adulthood, survival probabilities were 86% at age 30 years and 37% by age 52 years, with worse outcomes for patients developing the disease before the age of 5 years or with new disease features in adulthood. Nine asymptomatic mutation carriers with a median age of 13.5 years were identified. Conclusions: Our study demonstrates the variable nature of XIAP deficiency, which evolves over life for individual patients. Better therapeutic strategies and prospective studies are required to reduce morbidity and mortality and improve decision making and long-term outcomes for patients with XIAP deficiency. (J Allergy Clin Immunol 2022;150:456-66.) Show less
Stoep, M.Y.E.C. van der; Oostenbrink, L.V.E.; Bredius, R.G.M.; Moes, D.J.A.R.; Guchelaar, H.J.; Zwaveling, J.; Lankester, A.C. 2022
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non... Show moreAllogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT. Show less
Background: Proteasome-associated autoinflammatory syndromes (PRAASs) form a family of recently described rare autosomal recessive disorders of disturbed proteasome assembly and proteolytic... Show moreBackground: Proteasome-associated autoinflammatory syndromes (PRAASs) form a family of recently described rare autosomal recessive disorders of disturbed proteasome assembly and proteolytic activity caused by mutations in genes coding for proteasome subunits. The treatment options for these proteasome disorders consist of lifelong immunosuppressive drugs or Janus kinase inhibitors, which may have partial efficacy and noticeable side effects. Because proteasomes are ubiquitously expressed, it is unknown whether hematopoietic stem cell transplantation (HSCT) may be a sufficient treatment option. Objective: Our aim was to report the case of a young boy with a treatment-resistant cutaneous vasculitis that was initially suspected to be associated with a gene variant in SH2D1A. Methods: Whole-exome sequencing was performed to identify the genetic defect. Molecular and functional analyses were performed to assess the impact of variants on proteasomal function. The immune characterization led to the decision to perform HSCT on our patient and conduct follow-up over the 7-year period after the transplant. Because loss of myeloid chimerism after the first HSCT was associated with relapse of autoinflammation, a second HSCT was performed. Results: After the successful second HSCT, the patient developed mild symptoms of lipodystrophy, which raised the suspicion of a PRAAS. Genetic analysis revealed 2 novel heterozygous variants in PSMB4 (encoding proteasomal subunit beta 7). Retrospective analysis of patient cells stored before the first HSCT and patient cells obtained after the second HSCT demonstrated that HSCT successfully rescued proteasome function, restored protein homeostasis, and resolved the interferon-stimulated gene signature. Furthermore, successful HSCT alleviated the autoinflammatory manifestations in our patient. Conclusion: Patients with treatment-resistant PRAAS can be cured by HSCT. Show less
Bakunina, K.; Putter, H.; Versluis, J.; Koster, E.A.S.; Holt, B. van der; Manz, M.G.; ... ; Wreede, L.C. de 2021
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to... Show moreClofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events. Show less
Hepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral... Show moreHepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral hepatitis). In this situation, hematopoietic stem cell transplantation (HSCT) might be a curative option. Here the authors report on 6 patients who received HSCT after LT for nonviral HAAA hepatitis. The outcomes were interpreted in the context of recently reported immune suppressive therapy (IST) outcomes in 8 patients with HAAA and to HSCT outcomes in patients with HAAA who recovered from hepatitis without undergoing LT. All patients transplanted by using HLA-identical sibling donors (3 of 6) were alive and had normal liver function and hematopoiesis without graft versus host disease. Both patients receiving bone marrow from a matched unrelated donor (MUD) experienced extensive graft versus host disease that was fatal for one patient. Thereby, the authors conclude that HSCT can be considered as a first-choice treatment for this category of patients when HLA-identical donors are available. When no HLA-identical donor is available, IST should be applied as HSCT with other donor sources might be reserved for IST nonresponders or poor responders. Show less
BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural... Show moreBACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease.OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables.METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients.RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive.CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival. (C) 2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology Show less
In this thesis, we have explored the mechanism of minor H antigen-related GVHD. Hereto, we developed and validated new methods to detect and to phenotype minor H antigen-specific T cells on cryo... Show moreIn this thesis, we have explored the mechanism of minor H antigen-related GVHD. Hereto, we developed and validated new methods to detect and to phenotype minor H antigen-specific T cells on cryo-preserved human tissues. Using these methods, we investigated the influence of the ubiquitously expressed minor H antigen HY in skin GVHD. This first report on the in situ detection of skin-infiltrating HY-specific T cells in GVHD affected tissue of pediatric patient__s points to an active role of these T cells in the pathophysiology of acute GVHD after gender mismatched HSCT. Using our skin explant methodologies, we also aimed at gathering insights into the postulated involvement of hematopoietic-system restricted HA-1 in GVHD. This study was challenged by the contradictory results of clinical studies on the influence of HA-1 with GVHD. We showed that recognition of skin samples reconstituted with mature DCs, facilitated infiltration and local activation of HA-1-specific T cells. Although the infiltrated and activated HA-1-specific T cells did not cause skin tissue destruction in our model, our results provide a first step in understanding the reported association of HA-1 mismatching with clinical GVHD. Finally, we performed a large multi-center population-based study comprising 849 HSCT pairs, investigating the effect of broadly expressed and hematopoietic restricted minor H antigen-mismatching on GVHD and on relapse incidence after HLA-matched and HLA-identical HSCT. We showed that mismatching for broadly expressed autosomally encoded minor H antigens is associated with increased GVHD in HLA-identical, but not in HLA-matched unrelated HSCT. Disparities between donor and recipient for hematopoietic system-specific autosomally encoded minor H antigens do neither influence the development of GVHD nor had an effect on relapse incidence. Importantly however were the significantly lower relapse rates and disease free survival observed in those patients who suffered from GVHD. Show less
Laheij, A.M.G.A.; Soet, J.J. de; Borne, P.A. von dem; Kuijper, E.J.; Kraneveld, E.A.; Loveren, C. van; Raber-Durlacher, J.E. 2012
